Human immunodeficiency virus (HIV), the etiological agent of acquired immunodeficiency syndrome (AIDS), enters cells by binding its envelope glycoprotein (Env) to receptor molecules and fusing its membrane with the cell membrane. Understanding how receptor molecules mediate HIV entry is critical for elucidating the mechanisms of HIV infection and design of new antiretroviral treatments. We discovered important interactions of the receptor molecules with the HIV-1 Env. We found that CD4 is constitutively associated with CCR5 in the absence of gp120 or any other receptor-specific ligand. This interaction most likely occurs via the second extracellular loop of CCR5 and the first two domains of CD4. It can be inhibited by HIV-1 blocking monoclonal antibodies indicating a role in virus entry. These findings suggest a possible pathway of HIV-1 evolution and development of immunopathogenicity, and a potential new target for antiretroviral drugs. The constitutive association of a seven-transmembrane-domain G- protein-coupled receptor with another receptor also indicates new possibilities for cross-talk between cell surface receptors. Currently, we are further characterizing the interactions in the oligomeric HIV-1 Env-CD4-coreceptor complex leading to entry which is our major research goal for the next year. We also found that inefficient interactions of CXCR4 with CD4-gp120 complexes correlate with their inability to suppport HIV-1 envelope glycoprotein-mediated fusion. These results suggest a new mechanism of cell resistance to HIV-1 entry. Z01 BC 10257-04 - AIDS, membrane proteins, receptors, theoretical biology, Virus-Cell Interactions, - Human Subjects